Compounds for use in radiography



Patented May 9, 1944 COMPOUNDS FOR USE IN RADIOGRAPHY William H. Strain, John T. Plati, and Stafford L. Warren, Rochester, N. Y., assignors of one-half to Noned Corporation, Rochester, N. Y., and one-half to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing. Application June '11, 1940,

Serial No. 339,912

9 Claims. (01. 260-476) This invention relates to the manufacture and the use of halogenated aryl acids and esters and/ or salts thereof, and especially to esters of iodinated phenyl aliphatic acids, as contrast media for radiography, Roentgenography, or skiagraphy.

Prior to our invention there have been used in the art; certain halogenated vegetable oils such as iodinated rapeseed, poppyseed, or chloroiodihated eanut oil for the production of such radiopacity. Such preparations suiTer from the defects that they are rather viscous and cannot be sterilized. Furthermore, when they are introduced into certain cavities of the body such as the subarachnoid space of the spinal column or the brain cavity, these compounds are not eliminated by the body and through their continued presence may cause serious damage to vital parts.

It is apparent that the development of new compounds which may be employed as liquid contrast media in radiography is a highly desirable result. We have found a number of new compounds and methods of manufacture therefor, which compounds possess advantages when used as contrast media in radiography, a will be described in detail hereinafter.

This invention has for one object to provide a number of new'esters. Still another object is to provide novel esters of halogenated aryl acids. Still another object is to provide novel'esters which possess considerable utility for use as contrast media in radiography. Still another object'is to provide certain novel esters which are capable of being substantially eliminated after being introduced into certain body cavities. Still another object is to provide a plurality of organic acids from which said esters and/or salts may be produced.

Still another object is to provide methods for the manufacture of halogenated phenyl fatty acids. Another object is to provide methods for manufacturing esters from said acids. Still another object is to provide a suitable method for isolating and purifying the aforementioned novel esters. Other objects will appear hereinafter.

f Our invention may be generically described by the following structural formula:

X-(CH?) ,1COC R1 halogen m in which X represents a methylen (GI-I2) group or a methylene'group, monoor di-, substituted byalkyl, aralkyl, aryl, oxyalkyl, etc.,- -oxygen (O), sulphur (S), etc.; the "chain described as (CH2)n-l may be straight or branched; R1 may be methyl, ethyl, lauryl, dimethylene, methyleth-l ylene, trimethylene, and the like; n may bev any integer,usually less than 20 m may be 1, 2 or 3,- depending on the nature of R1; and the aromatic ring will be substituted by one or more halogen atoms, particularly by iodine, and may also be substituted by alkyl; aralkyl, aryl, or alkoxy groups; further the aromatic ring may bepart of a condensed ring system.

The esters claimed in this invention are, for the most part, free-flowing new liquids and are suited particularly'for the production of radio-j pacity in those parts of the body where thereare natural cavities, or where cavities have been produced either by accident or by operation. The compounds may be used also for arteriographyand venography, preferably, when administered in emulsified form.

Our invention is further illustrated by the fol-: lowing examples which are given by Way of illus tration of Our preferred embodiment:

Example 1 To a mixture of parts of w-phenylbutyric acid, 68 parts of powdered iodine,.800 volumes of glacial acetic acid, and 80 volumes of concen-j trated sulfuric acid, 80 parts of sodium nitrite are added. The mixture'is stirred-and boiled-for one-half hour, at the end of which time 8- parts ofsodium nitrite is. added over a period of 10- minutes, and the-'mixturestirred and boiledfor. about 10 minutes more. The hot mixture is drowned in 100. parts of ice and, parts-of water containing a small amount of sodium bisulfite, On standing, the precipitated acids soe lidify and are filtered off. After drying by distilling toluene from the moist cake, the product is converted to the ethyl ester by reacting with ethyl alcohol. The ester so obtained is a mixtureboiling at -158/ 1.5 mm. and has a density of about 1.5/20 C.

This ester product is improved and purified by hydrolysing with alcoholic alkali, precipitating the liberated acid, and crystallizing the latter from high boiling li-groin. The w-(4-iodophenyD-butyric acid is thus obtained in fair yield as white crystals melting at 88.5-89.5 C. On ester--' ifying with ethyl alcohol byreaction therewith,

ethyl w-( l-iodophenyl) -butyrate, boiling at'145- 148/03 mm. with a specific gravity of 1.49/

results.

When this compound is injected, for example, intraperitoneally in rats, it is well tolerated in doses of 2.2 g./kilogram but in doses of 3.0 g./kilogram per cent of the animals are killed. Ra-

.diographs taken of these test animals show dense shadows at the time of injection and disappearance of these shadows at the end of 3 days.

.yield, is a white crystalline compound melting Example 2 The following represents our preferred compound and its preparation. To a mixture of 576 parts of w-phenylValerlc acid, .4041parts of powdered iodine, 5760 volumes of glacial acetic acid. and 576 volumes of concentrated sulfuric acid. 517 parts of sodium nitrite are added. The mixture is stirred and boiled until the mixture becomes pale yellow in color. The hot mixture is poured into 7000-8000 parts crushed ice and stirred vigorously. Afterthe ice has melted, the yellow precipitate is filtered, and the o-(4-iodophenyl) -valeric acid purified by crystallizingfirst from-high boiling ligroin and then from per cent acetic acid. The pure acid is obtained in good yield andmelts at .109.5- 110.5 C. On esteriiication with ethyl alcohol by reaction therewith,-ethy ar-(4-iodophenyD-valerate of boiling point- '158 0.12 mm. and of specific gravity 1.44/20" C. isobtained.

When this compoundis injected intraperitoneally in rats, it is well tolerated in doses of" 2.5 g.-/kllogram but in does of 3.0 g-./kilog-ram 50 per cent of the animals are -killed.- Radiographs taken of these test animals at the time of in- 1 jection show dense shadows at the site of injection and disappearance: of these shadows at the-nd of 3 days. When the compound is injected in thesubarachnoid space of the spinal column of dogs, the compound is fairly well tolerated in doses of 0.3 g./kilogram.anddisappears fromthe spinal column within six weeks. It is desired to emphasize in particular that it is in this respect. that, our novel compounds represent a great advance as compared with prior art agents. As already pointed out, prior art agents after injection, may not be eliminated and consequently may causedamage at a later time. During this time, the dogs are usually clinically well. Radiograph'staken of such dogs reveal denseshadows in the spinal column. By tiltingthe animal, the position of radiopaque materialmaybe varied at will.

' Ethyl wi l iodophenyll -valerate is particularly satisfactory for outlining human nasal and other sinuses The compound produces clean shadows in theradiograph and is-readily eliminated from the sinuses.

.The ester when. injected in the- Fallopian tubes delineates the structures of thesepassages very graphically when av radiograph is taken. The ethyleneglycoL. propylene glycol, trimet-hylene lycol, and. glyceryli esters 0t w-(4-iodophenyl) valeric acid are moreyiscousthan the ethyl ester and are suited for injection in sesame oil solution; into the human bronchial tubes for the production of radiopacity.

Example 3 To a. mixture f-2&5 partsof w-phenylheptoic acid; 17.6,parts of powdered iod e 300 volumes oi glaciaiiacetic acid audit-9 volumes of concentrated sulfuric acidr27 parts of. sodiumnitrite areadded. The mixture is stirred and boiledfor at 93-945 C. On esterification with ethyl alcohol in the usual manner, ethyl w-(iod0phenyl)- heptoate of boiling point 175-177 C./2.5 mm. and

. of specific gravity 1.36/20, is obtained.

When this ethyl ester is injected in the sub arachnoid space of the spinal column of dogs, the compound is fairly well tolerated in doses of 0.3 g./kilogram and disappears from the spinal shadows in the spinal column.

T,' lecithin," emulsions are very stable and maybe sterilized.

column after about six weeks. During this time the dogs are usually clinically well. Radiographs taken of these experimental dogs reveal dense By tilting the animal, the position of the opacity may be varied at, will.

' Example 4 I cooled mixture of 52.5 parts of aluminum chloride and volumes of iodobenzene. The mixture is decomposed with cracked ice and dilute hydrochloric acid. The iodobenzene layer is washed with sodium bisulfite solution and with water, and then distilled. The composition of matter having the probable formula, ethyl 4-iodophenyl-undecylate, is a colorless liquid boiling at 196-198/1 mm., and of specific gravity of 1.26/ 20 C.

' Ethyl 4-iodophenylundecylate is readily emulsified when it is passed through an homogenizer with an equal Weight of water containing a small amount of a dispersing agent such as Igepou Aerosol, etc. The resulting Such an emulsion is particularly suited for rendering the veins radiopaque. The emulsions usuallyproduce an immediate sense of discomfort but this is transient. Large quantities maybe given without toxic'effects. For example, three doses of 20 cc. each of a 50'per cent emulsion were administered to a dog weighing 20 kg, two of the doses being given within two hours of each other and the third dose on the following day. The dog was nauseated when the second dose was given but otherwise was in good clinical condition and subsequently showed no ill effects.

Example 5 77.6. parts of ethyl oleate is introduced gradually at5-8f C.. during 1 hour into a well-cooled mixture. of 114 volumes of iodobenzene and 53 parts of aluminum chloride. The iodobenzene layer is washed with sodium bisulfite solution and with water, and then distilled under vacuum. The ethyl iodophenylstearate. boils at about 250 C./2.5 mm. and has a specific gravity of l.O9/20 C. The compound is suitable for the production of opacity in the lungs.

The preceding compounds represent our preferred embodiment because of their capability of varied use, as in subarachnoid spaces. However,

, We have discovered other esters which also produce radiopacity and have certain utility, exem'' plifled by the following:

' Example 6 Into a mixture of 25 parts of 2,3,5-triiodobenzoic-acid and 500-volumes of methyl alcohol, a current of dry hydrogen chloride was'passed for 3-4 hours. During the course of the introduction of the hydrogen chloride the mixture became warm, and the undissolved acid went into solution. The mixture was allowed to stand for several days at low temperature, and was then filtered. A good yield of crude methyl 1,2.,3,5- triiodobenzoate is obtained. The product was purified by distilling at low pressure. Pure methyl 2,3,5-triiodobenzoa-te of B. P. 240-24471!) mm. and M. P. 104-105 was obtained. A solution of this ester was prepared by dissolving in warm sesame oil. This solution is suitable for use in renderingthe bronchial passages and other portions of the respiratory tract opaque to X-rays.

Example 7 Methyl 2,5-diiodobenzoate was prepared from 2,5-diiodobenzoic acid according to the directions given above.- The pure ester was obtained by use in rendering the Fallopian tubes and pron-- chial passages opaque to X-rays.

Our alkyl halogenophenyl fatty acid esters,

particularly the novel iodinated derivatives of our invention, possess superior qualities not enjoyed by the iodinated or the chloroiodinated vegetable oils. They are mobile, stable compounds which may be sterilized, and certain of oils aforementioned. The solid preparations;

must all be administered in a liquid vehicle such I,

as sesame oil or some other inert oil which is readily absorbed by the tissues.

In the foregoing examples wherein we have referred to the reaction of the haolgenophenyl fatty acid with alcohol this may be accomplished in various Ways and under various conditions of,

catalyst and the like; (kindly see Unit Processes by Groggins, Chapt.

pressure, temperature,

X, wherein a variety of conditions and apparatus? are shown) of which the aforementioned exam-j ples are merely illustrative, and we do not wish to be restricted in this respect.

For example, an acid produced by our process may be reacted with monohydric alcohols, dihydric or other polyhydric alcohols, glycol others, mixed esters, anhydrides or other compounds, The reaction may be accomplished merely by heating the ingredients together with refluxing," However, if desired, catalysts, water removing{ compounds, reduced pressure and the like may be employed. While we do not wish to be unduly bound in our views, we believe that the solubility, the rate of elimination, and comparable properties of our novel compounds may be governed to a substantial extent by the chain length; v

that is the short chain compounds may be more ple, for compounds which are to be injected into the spinal column, not only an ester which has some degree of permanence is desired, but, however, one Which is eliminated gradually, for ex ample, over several months.

In the operation of our processes in place of the ligroin various other petroleum fractions may be used or solvents such as aliphatic acids (acetic acid), alcohols and the like may be .employed. While we prefer to employ iodine as the halogen, other halogens, as for example bromine derivatives, may be employed in some instances. However, chlorine and fluorine derivatives are poor contrast agents and hence iodine and bromine are distinctly preferred. Certain other changes may be made in our process and products such as for example: Our compounds may be prepared by nitrating the phenyl-acid compound followed by reduction, diazotization and treatment with an alkali or copper halide. That is, nitratedphenyl valeric acid may be reduced and the amino compound diazotized and treated with potassium iodide. Or, a halogenated benzene may be reacted with a dibasic anhydride and the resulting ketoacid reduced to a halogenated phenyl fatty acid. For example, iodobenzene may be reacted with succinic anhydride in the presence of aluminum chloride (or other similar condensing agent) and the product may then be reduced by Clemmensen reduction to iodophenylbutyric acid. Or, for example, iodobenzene may be reacted with an ester such as the ethyl ester of unsaturated fatty acids, the reaction being carried out in the presence of aluminum chloride or othersimilar condensing lehgient as zinc chloride, ferric. chloride, or the While the compounds in the aforementioned examples, particularly those having a five to eleven carbon intermediate chain (valerates, etc), are preferred because of their special properties of having low toxicities and of being readily eliminated, etc., our compounds may be modified in such chains. FOr example, intermediate oxygen groups might be substituted of which the following are examples:

Q0 (CHz)a-C o 0 Et Q o cum-o o 0 Et An application of the iodinatedacids described in this invention consists in using their metallic salts, particularly their sodium salts, for retrograde pyelography. In this connection the iodophenylated aliphatic acids in which the side chain is short are of paramount interest because of their higher iodine content. Thus, aqueous soltion of sodium, iodobenzoate (iodophenyl formate), sodium iodophenyl acetate, and sodium iodophenoxyacetate are well adapted for retrograde pyelography.

By the term radiographic contrast media," we refer to the use of our novel substances in all branches of radiological practice such as radiography, diagnostic radiology. Roentgenography and skiagraphy,. myelography'. and the like fields.

It is, therefore, apparent from the foregoing that our invention is susceptible of some modification; hence, we do not wish to. be restricted excepting insofar as may be necessitated .by-the prior art and the spirit of the appended claims.

What we claim and. desire to secure by Letters Patentof the United States of America is '1. The compound ethyl iodophenylvalerate having a boiling point of approximately 158, C./2 mm. and a. specific gravity of about 1.4/20. C.

2. Ethyl iodophenylundecylate having a boiling point of 196-198 1 mm. and a specific gravity of about 1.26/20. v

3. Esters of phenyl fatty acids wherein the phenyl group contains from 1 to 3 iodine atoms as a nuclear substituent, and wherein the ester groirpfis sel'ectedlfromthe group consisting of a lower saturated alkyl group, a lower. saturated hydroxyalkyl group, and a lower saturated dihydroxyalkyl group, and wherein the fatty acid group is selected from the group consisting'of the residues of saturated fatty acids having a chain length of not less than 4 and not more than 18 carbon atoms, l

4. The compounds having the general formula:

wherein 1: represents a whole number not greater than 3, R represents a member selected'from the group consisting of saturated acyclic hydrocarbon groups having not less than 4 and not more than 18 carbon atoms and R1 represents a member selected from the group consisting of a lower saturated alkyl group, a lower saturated hydroxyalkyl group and a lower saturated dihydroxyalkyl roup.

5. The compounds having the general formula:

wherein R: represents a member selected from the group consisting of saturated acyclic hydrocarbon groups having not less than 4 and not more than 18 carbon atoms, and R1 represents a member selected from the group consisting of a lower saturated alkyl group, a lower saturated hydroxyalkyl group and a lower saturated dihydroxyalkyl group. r i

6. The compounds having the general formula:

O-leo o 0 R1 wherein R represents a member selected from the group consisting of saturated acyclic hydrocarbon groups having not less than 4 and not more than 18 carbon atoms, and R1 represents a member selected from the group consisting of a lower saturated alkyl group, a lower saturated hydroxyalkyl group and a lower saturated dihydroxyalkyl group. I 1 v 7. The compounds having the general formula:

lO-onm o o o n,

wherein n represents a whole number selected from the group consisting of numbers not less than 4 and not more than 18 and R1 represents a member selected from the group consisting of a lower saturated alkyl group, a lower saturated hydroxyalkyl group and a lower saturated dihydroxyalkyl group.

8. The compounds having the formula:

9. The compounds having the formula:

IO-OWHQPC 0 0 cans WILLIAM H. STRAIN. JOHN T. PLA'II. STAFFORD L. WARREN. 

